10-68122195-G-C

Variant names:

• chr10-68122195-G-C
• rs201983087
• NM_032578.4:c.757G>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS1_Supporting

The NM_032578.4(MYPN):​c.757G>C​(p.Gly253Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00011 in 1,609,532 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. G253G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: MYPN NM_032578.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 5.01
• Publications: 0 publications found

Genes affected

MYPN (HGNC:23246): (myopalladin) Striated muscle in vertebrates comprises large proteins which must be organized properly to contract efficiently. Z-lines in striated muscle are a sign of this organization, representing the ends of actin thin filaments, titin, nebulin or nebulette and accessory proteins required for structure and function. This gene encodes a protein which interacts with nebulin in skeletal muscle or nebulette in cardiac muscle and alpha-actinin. In addition, this gene product can interact with a protein with the I-band indicating it has a regulatory as well as structural function. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2011]

MYPN Gene-Disease associations (from GenCC):

• MYPN-related myopathy

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• cap myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• childhood-onset nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated restrictive cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• dilated cardiomyopathy 1KK

  Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15354842).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0000788 (12/152322) while in subpopulation NFE AF = 0.000147 (10/68034). AF 95% confidence interval is 0.0000791. There are 0 homozygotes in GnomAd4. There are 7 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032578.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYPN	NM_032578.4	MANE Select	c.757G>C	p.Gly253Arg	missense	Exon 2 of 20	NP_115967.2
	MYPN	NM_001256267.2		c.757G>C	p.Gly253Arg	missense	Exon 3 of 21	NP_001243196.1
	MYPN	NR_045663.4		n.994G>C		non_coding_transcript_exon	Exon 2 of 18

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYPN	ENST00000358913.10	TSL:1 MANE Select	c.757G>C	p.Gly253Arg	missense	Exon 2 of 20	ENSP00000351790.5
	MYPN	ENST00000540630.6	TSL:1	c.757G>C	p.Gly253Arg	missense	Exon 1 of 20	ENSP00000441668.3
	MYPN	ENST00000613327.5	TSL:1	c.757G>C	p.Gly253Arg	missense	Exon 3 of 21	ENSP00000480757.2

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000688 AC: 17 AN: 247048 AF XY: 0.0000674

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.0000295

Gnomad ASJ exome AF: 0.000210

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000116

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000113 AC: 165 AN: 1457210 Hom.: 0 Cov.: 31 AF XY: 0.000105 AC XY: 76 AN XY: 724516

African (AFR) AF: 0.00 AC: 0 AN: 33260

American (AMR) AF: 0.0000226 AC: 1 AN: 44166

Ashkenazi Jewish (ASJ) AF: 0.000350 AC: 9 AN: 25720

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 85656

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53256

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.000132 AC: 146 AN: 1109600

Other (OTH) AF: 0.000150 AC: 9 AN: 60140

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152322 Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7 AN XY: 74478

African (AFR) AF: 0.00 AC: 0 AN: 41562

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.0000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000741 AC: 9

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Jul 17, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function

Apr 27, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MYPN c.757G>C; p.Gly253Arg variant (rs201983087), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 222748). This variant is found in the non-Finnish European population with an allele frequency of 0.011% (14/127,482 alleles) in the Genome Aggregation Database. The glycine at codon 253 is weakly conserved, and computational analyses predict that this variant is neutral (REVEL: 0.11). Due to limited information, the clinical significance of the p.Gly253Arg variant is uncertain at this time.

Dilated cardiomyopathy 1KK;C4479186:MYPN-related myopathy Uncertain:2

Aug 03, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 05, 2022

Clinical Genomics Laboratory, Stanford Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gly253Arg variant in the MYPN gene has not been previously reported in association with disease. This variant has been identified in 14/127482 European (non-Finnish) chromosomes (18/278450 chromosomes overall) by the Genome Aggregation Database (http://gnomad.broadinstitute.org/) Although this variant has been seen in the general population, its frequency is low enough to be consistent with the prevalence of cardiomyopathy. This variant is present in ClinVar (Variation ID: 222748). Computational tools predict that this variant does not impact protein function; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Gly253Arg variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: BP4]

Left ventricular noncompaction cardiomyopathy Uncertain:1

Nov 05, 2015

Blueprint Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dilated cardiomyopathy 1KK Uncertain:1

Jan 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 253 of the MYPN protein (p.Gly253Arg). This variant is present in population databases (rs201983087, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MYPN-related conditions. ClinVar contains an entry for this variant (Variation ID: 222748). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Cardiovascular phenotype Uncertain:1

Dec 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G253R variant (also known as c.757G>C), located in coding exon 1 of the MYPN gene, results from a G to C substitution at nucleotide position 757. The glycine at codon 253 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	23
DANN	Benign	0.86
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.2	L
PhyloP100		5.0
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.11
Sift	Benign	0.18	T
Sift4G	Benign	0.43	T
Polyphen		0.81	P
Vest4		0.44
MutPred		0.21		Loss of glycosylation at S257 (P = 0.1477)
MVP		0.78
MPC		0.17
ClinPred		0.13	T
GERP RS		5.7
Varity_R		0.17
gMVP		0.39
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs201983087; hg19: chr10-69881952;